Emil fischer



UNITED STATES P TENT OFFICE.

EMIL FISCHER, OF BERLIN, GERMANY, ASSIGNOR TO 0. F. BOEHRINGER &SOEIINE, OF WALDHOF, GERMANY.

ALKYL-PURiN AND PROCESS OF MAKING SAME;

SPECIFICATION forming part of Letters retent No. 617,985, dated January17', 1.399. Application filed September 7, 1897. Serial No. 650,826.(Speeimena 1'0 all whom it may concern:

Be it known that I, EMIL FISCHER, a citizen of Germany, residing atBerlin, Germany, have invented certain new and useful Improvements inthe Preparation of Alkylized Oxypurins; and I do hereby declare thefollowing to be a full, clear, and exact description of the invention,such as will enable others skilled in the art to which it appertains tomake and use the same,

This invention relates to the preparation of alkylized oxypurins, andmore particularly the syntheticalproduction of heteroxanthin,paraxanthin, and methylized hypoxanthins, all of'wl ieh have beenrecognized as methylized oxypurins as a result of recent investigations.- So far as I am aware these bodies have hitherto been obtainedonly as secretions formed in the animal organism. No one has hithertoproduced them artificially or synthetically.

lleteroxanthin, as a result of the researches of Kruger and Salomon, hasbeen recognized as monomethyl-xauthin. (See Zez'tschriftfilrIhysiologische Clzemie, Vol. 21, page 169.) As to paraxanthin it wasconjectured that the same was identical with the last of thedimethyl-xanthins. However, no direct proof existed for thissupposition. The constitution of hypoxanthin was still less understood.

I have discovered methods of producing both heteroxanthin andparaxanthin, as well as dimethyl-hypoxanthin described by Krilger, and,finally, the hitherto unknown body monomethyl-hypoxa'nthin fromtheobromin. My invention consists in these methods and such otherfeatures, subprocesses, and compounds as will be herelnafter set forth,and pointed out in the claims.

In explaining my invention the nomenclature recently proposed by me(Sifzzmgs Berichfe der Ifonig/l, lreussisehen Alca'demic 1897, N0. 1,Jan. 8, 1897, and Bcrichic del- Denis-chem O/lemLw-he/L Gcsellschofl,Vol. 30, No. 5, page 557) and the structural formulae, as the result ofthe most recent investiga tions, will be adopted. According to thisnomenclature the various atoms of the purin molecule which forms thebasis of the uric acid and xanthin molecules and many others arenumbered as follows:

on 0 a Bearing these numerals and their relative positions in mind, thedesignations of the equivalent terms hereinafter used in connection withheteroxanthin, paraxanthin, and the hypoxant-hins will be apparent andread- I ily understood. The structural formulazand consequent additionaldesignations which may be applied to these compounds are as follows:

First. Heteroxanthin purin Third. '7-methyl-hypo IIN-CO xanthin or7-methyl-G-oxypurin IIC G--N.CII

Fourth. 1-7'dimethyle (1H,.N-CO

hypoxanthin or 1-7-dimethyl-6-oxypurin' IIC (J I.OH on In preparingthese bodies I start from theobromin, which is the same as3-7-dimethylxanthin s or 3-7-dimethyl-2-G=dioxypurin and whose formulais: V

treating the same with a phosphorous-oxyhalogen compound, such asphosphorous oxychlorid. Under this treatment the oxygen atoms arereplaced by chlorin and one methyl radical is split off, the resultantbody being Cl. 0 U -N. (Hid-EH 0 Second. '7 -n1ethyl-dichloropurin onbeing treated with alkali exchanges only one chlorin atom for hydroxyl,7-n1ethyI-G-oXy-Z- hloropurin being obtained:

' Third, 7= methyl-6-oXy-2-dichloropurin will readily take up an alkylradical in the imido group. For example, when subjecting the same tomethylation it yields 17-dimethyl-6-" oxy-Q-chloropurin, thus: IIN CO01.0 (J-N.CI.I +OII I+KOIIZ II II NO-'N CIl .NCO 30 01.0 C-'N.Cll +KI+IIOl H l W 5 N-*(J-N Fourth. 17*dimethyl-6-oxy-2-chloropurin is convertedinto paraxanthin by heating it with hydrochloric acid: 0 on aiwoo 9 C11ON.CH +II ,O:

l l 11 l l a a N-C -N CII N- CO oo o-No1I;,+uo1.

Cll HN-C-N Fifth. 7-methyl-6-oXy-f2ch1oropuriniscon- Io verted into 7methyl-hypoxanthin by a reducing agent, such as hydriodic acid:

IIN-GO l l a 01.0 CN.OII 3+2HI:

vH I lIN-CO 5 no CI\'.ClI +IICl+I.

gester-together with one hundred parts of phosphorous oxychlorid, to ate m peratu re of 140 centigrade, this temperature being maintained forthree hours and the mass constantly agitated. A clear liquid having apale-brown color results. From this liquid the remaining phosphorousoxy'chlorid is removed by distilling in vacuo. One hundred and fiftyparts of cold water having a temperature of between 0 and 5 centigrade,preferably, are then poured over the amorphous residue. Under thistreatment the mass is gradually converted into almost-colorlesscrystals. This change is hastened by shaking. The generation of heat inthe mass is obviated by cooling with ice or other refrigerant agency.The mass after having been finally cooled thoroughly is put on thefilter and washed with ice-water. The crude product so obtained iscontaminated with a substance which is soluble in alkali. The same ishence dissolved out with an alkaline solution, preferably very dilutesoda lye of about one per cent. strength. The solid residue isthendrained on a filter and well washed thereon and redissolved in hotwater and recrystallized therefrom. The new compound,7-methyl-2-6-dichloropurin, so obtained crystallizes in fine colorlessneedles,

- which melt at about 196 to 107 centigrade.

It is soluble with difficulty in cold water and soluble in about seventyparts hot water and in about thirty parts boiling alcohol. Itscomposition is indicated by the formula G l I N Cl or the structuralformula:

ore o-non,

equation:

HN-OO 3 0o c riou +2roou:

CII orI,N--o-N v3 ore ()-NCH3 +u ro H on +(on,o ,,ro. L N-(L-N511-011 1. lrepu/Hliou of lIF/JI'H-l'l!IIHLtIL-I take one part ofT-methyl-2-(3-dichloropurin and heat the same under pressure-r. g., in apressure-tube-togcther with ten parts of hydrochloric acid of thespecific gravity 1.10, to from 120 to 125 centigrade, maintaining thistem mrature for three hours. A clear faintly-colored solution results,which on being evaporated to dryness on the water-bath leaves thehydrochlorate of the paraxanthin or methyl-xauthin in the shape ofcoarse prismatic crystals. The reaction takes place according to thefollowing equation:

To liberate the base heteroxanthin dilute ammonia is poured over thesecrystals in suflicient or more than sufficient quantity to combine withall of the 1101. Any excess of ammonia is removed by evaporation. Thediificultly-soluble base is then drained on the filter and redissolvedin hot water, the solution being then allowed to cool. The base is thusobtained as a colorless indistinctly-crystalline powder. To obtain thebase in an absolutely pure condition, it is purified by first preparingthe sodium salt which forms good crystals.

The heteroxanthin or 7 -methy1-xanthiu or 7-methyl-2-6-dioxypurincoincides in most respeets with the heteroxanthin which has beeninvestigated and described by Kruger and Salomon,(Zeiischrlflfiirllzysiologyische Chcmir, Vol. 21, page 169,) as well asBondzynski and Gottlieb,(Berir7lte dei-Druischcn Chemz'sohcnGesellsrhqf't, Vol. 28, 1895, page 1113, and Archie. filr Emporium-MulePufleoIog z'e and P/mrn'mzir, Vol. 37, page 385.) A difference was,however, observed with regard tothe melting-point and the solubility ofthe base in water, the varying data found by the former investigationsbeing due to the impurity of the ingredients or reagents employed.

I find that pure heteroxanthin has no fixed ing the preparation of twonew compounds first prepared and discovered by me. These subprocesses,stated in the order in which they are carried. out, are (a) thepreparation of 7 methyl 6 oxyi3 chloropurin (b) the preparation of1-7-dimethyl-d-oxy Q-chloropurin, and conversion of the latterintoparaxanth in.

(u) Prcpma/[on (IfT-lluU1j/Z-(i-0J?y-i?C7LZO7 O en parts of finelypulverized 7- methyl-Q-G-dichloropurin, which has been described underthe first head, are suspended in one hundred parts of boiling water anda quantity of soda-lye sull'icient to furnish two molecules of thealkali for each molecule of the mcthyl-dichloropurin. The mass is thenstirred nntila clearsolution is formed, whereby the end of the processis indicated. The reaction takes place according to the followingequation:

Cl. C G-N. Ull +2Na Oil:

The liquid is then cooled and the same is then supersaturated withacetic acid, whereby the methyl-oxypurin is precipitated in crystal lineform. This precipitate afterbeing'separated is boiled in one hundred andfifty parts of water, and after boiling it is filtered and the filtrateallowed to cool, when the new lure meihyl-oxychloropurin attains ayollow color when heated in about: Z310" contigrade. At a highertemperature its color bccomcs more and more dark, this darkening beingattended by continuing decomposition. it dissolves in about one lnn drcdand fifty This process proceeds in accordance with the equation:

IIN- CO Cl. C G.N.OH +KOH:

r I ou+icn N- C *-N On cooling, the new dimethyl compound separates fromthe liquor in the form of iine white acieular crystals. These crystalsare then recrystallized from water for the purpose of furtherpurification. An analysis of the pure compound gives figurescorresponding to the formula C II N OOL Its structural formula is foundto be:

1-T-dimethyl-G-oxy-2'chloropurin melts at about 270 centigradc, themelting being, however, attended by decomposition. It is soluble inabout fifty parts boiling water. It is not soluble in dilutealkalies,but soluble in concentrated hydrochloric acid.

(v) Jone-evasion of J-f-dimihyZ-U-ogcy-Q- chloropurin intoparaxlmlhin.One part of the 1-7-dimethyl-(i-oXy-2chloropnrin, togetherwith ten parts of concentrated hydrochloric acid of the specific gravity1.19, is heated to from 125 to 130 centigradc. .u ndcx pressurec. g., ina digester. This temperature 'is maintained for from two to three hours.

A clear solution results, and this evaporated to dryness.v Theparaxanthin,which is host purified by first convol-ting it into itssodium salt, which is soluble with dil'liculty, and then liberating theparaxanthin by rcdissolving the sodium salt in hot water andsupersaiuratiug with acetic residue is crude acid. The reaction proceedsaccording to the equation:

The analysis of the pure product thus obtained gives figurescorresponding to the formula C II NQ or the structural formulahereinabove given. The product thus synthet-icall y produced isidentical with the natural compound paraxanthin. Its melting-point is295 to 290 centigrade. It is soluble in about twenty-four parts of hotwater, and on rapidly cooling such solution it crystallizes the efrom inthe form of fine flexible needles. It forms a sodium salt which isdifiicultly soluble in an excess of cold soda-lye.

Fe 1/ r/h. Preparation of 7-methyZ-hypowan- [him-One part of7-methyl-G-oxy-iZ-chloropurin,which has been hereinabove described,

is mixed with eight parts of colorless hydrisodie'acid. of the specificgravity 1.06 by pouring the, latter over the former. Itis thenhc.'tted,to, from to centigrade, after having first added a half part ofphosphonium iodid, and maintained at this temperature and frequentlyshaken until a clear color less solution results. The liquid is thenevaporated,when the hydriodate of the 7-methylh ypoxanthin or7-methyl-6-oxypurin remains as a colorless crystalline niass,which isreadily soluble in water. The reaction proceeds according to theequation:

This new base, ii1etliyl-hypoxanthin, is liberated from the above saltby dissolving the latter in water and boiling the same, then addingcarbonate of lead to the boiling solution, and then filtering. Anytraces orsmall quantities of lead remaining in the filtrate are thenthrown out by means of hydrosulfuric acid, and the liquid is againliltered, after which the liltrate is evaporated to dryness. The residueis methyl-hypoxanthin and forms a colorless crystalline mass, which isredissolved in and crystallized from alcohol forthc pnrposeofpnrilicatioi'i. It is thus obtained in the form of lineeolorlessneedles.

Its analysis shows that its constitution corresponds to the formula C IINQ. Its structuralformula is: I

II N-CO IIU O--N.CII

l H CII N -(L-N Methyl-hypoxanthin when rapidly heated assumes, a browncolor at about 34:0" centigrade and melts at about 353 centigrade. Themelting-point, however, is not quite fixed. It is readily soluble inwater. On

adding nitrate of silver to an aqueous solu- I tion of thesameawhitepreeipitateisformed, which on being dissolved inwarm dilute nitric acidis obtained as a white crystalline powder.

1 Fifth. Preparation of .1-7-(1imeflzyZ-hyporunlhin.Two parts of'7-methyl-hypoxanthin, which has been described, are mixed with twentyparts of water, twenty parts of methyl alcohol, two parts of-methyliodid, and 0.3 parts of sodium dissolved into methyl alcohol, (aquantity sufiicient to replace the hydrogen represented by the one imidogroup in the formula of 7-methy1-hypoxanthin.)

C lI N O.NaI+3 aqn. is separated from the liquid in the form 0 needles.The base is separated from the sodium-iodin compound by'dissolving inwater and shaking with oxid of silver. After filtration of the iodid ofsilver the solution is evaporated and the base is then extractedtherefrom with chloroform. After the solvent has evaporated thedimethy1-hypoxanthin remains as a cystalline mass in the form of fineneedles. The former process proceeds according to the equation:

l)imethyl-liypoxanthin begins to soften at together.

about 24.3" centigrade and melts at 247 centigrade, withoutdecomposition. Ileated in small quantities it distils over withontdecomposition for the greater portion. From hot alcohol it crystallizesin the form of fine needles, which for the most part are massed In otherrespects this base is dis tinguished by the characteristic propertiesset forth by Kriiger.

lVhile I have herein described the process of preparing heteroxanthin or7-inethyl-2-6- dioxypuriu from T-methyl-Q-G-dichloropurin or indirectlyfrom th eobromin in illustration of my invention, I do not claim hereinthe same, since the same is made the subject-matter of my concurrentapplicationfierial No. 665,462, filed January 3, 1898, (No. 21;) nor doI in this application-lay claim to the new compound 7-methyl-hypoxanthinor 7-methyl-6- oxypurin and the process of preparing the same and ofconverting the same into 1-7-diinethyl-hypoxanthin or1-7-dimethyl-6-oxypurin, since said new compound and processes form thesub ject-matter of my concurrent aplication, Serial No. GU5AG3, filedJanuary 3, 1898, (No. 22,) and are herein described only in illustrationof my invention.

\Vhat I claim, and desire to secure by Letters Patent of the UnitedStates, is-- 1. The method of preparing 7-methyl-2-G- dichloropurinwhich consists in treating theobromin with an oxyhalogen compound ofphosphorus.

2. The method of preparing 7-methyl-2-6- dichloropurin which consists inheating theohromin with phosphorous oxychlorid.

3. The method of preparing 7-metl1yl-2-6- dichloropurin which consistsin heating theobrom in together with phosphorous oxychlorid underpressure, substantially in the proportions and at the temperaturestated, then re moving the excess of phosphorous oxychlorid and addingwater to the residue.

at. The method of preparing 7-niet-hyl-2-G- dichloropurin which consistsin heating theo bromin together with phosphorous oxychlorid underpressure substantially in the proportion and at the temperature stated,then removing the excess of phosphorous oxychlorid and adding water to*the residue, and then treating with alkali and filtering and washingthe residue and finally redissolving in hot water and allowing tocrystallize.

The method of preparing7-mcthy1-2-lldichlortunu'in which consistsiuheatingtheobrom in to ather with phosphorous oxyclilorid under p ,1substantially in the proportion and at moving the ei-Lccss ol'phosphorous oxychlcrid and adding: water to the residue, then treatingwith dilute soda-lyr-. I

(3. As a new chemical compound, 7-methylt ddich loropurin, having theformula'above given and having; the following properties: itcrystallizes in fine colorless needles, which .uielt at about 11% to197, centigradc; it is dillieulfy soluble in cold water and dissolvesthe temperature stated, then re-- in about thirty parts boiling alcoholand seventy parts hot water. '1

7. In the art of preparing methylized oxypurins, the process whichconsistsin treating 7-methyl-2-G-dichloropurin with an alkali. 8. Theprocess which consists in heating 7 1nethyl-2-6-dichlorop1irin withdilute alkali.

9. The process which consists in suspending pulverized 7-methyl-2tl-dichloropurin in boiling water and adding thereto soda-lye.

10. The process which consists in suspending pulverized7-methyl2-6dichloropurin in boiling water and adding thereto soda-lye,agitating the mixture and then throwing out the methyl-oxychloropurin byan acid such as acetic acid.

11. The process in the manufacture ofparaxanthin which consists intreating 7 -methyl- 6-oXy-2-chloropurin with a. methylating agent.

12.- The process which consists in treating 7-methyl-6-oxy-2 chloropurinwith an alkali together with methyl iodid.

13. The process which consists in dissolving7-niethyl-6-oxy-2-chloropurin in potashlye and adding methyl. iodid andheating the mixture, substantially as described. I

14. The process-which consists in treating l-7dimethyl-6-oxy-2-chloropurin with a mineral acid, whereby the same isconverted into paraxanthin 15. The process which consists in heating1-7-dimethyl-G-oxy-2-chloropurin with hydrochloric acid, for the purposeof converting the same into paraxanthin.

16. The process which consists in heating under pressure1-7-dimethyl-G-oxy-2-chloropurin together with concentrated hydrochloricacid.

17 The process which consists in heating under pressure1-7-diinethyl-6oxy-2-chloropurin together with concentrated hydrochloricacid and then purifying the paraxanthin by converting it into itssoda-salt.

18. The process for the preparation of paraxanthin which consists intreating 7-1nethyl- 2-6-dichloropurin with an' alkali then isolatin gthe resultant 7-inethyl-G-oxy-Q-chloropurin and methylating same, thenisolating the resultant 1'7--diinethyl-6-oxy-2-chloropurin and treatingthe same with amineral acid.

19. The process for the preparation of par-.

.axanthin which consists in treating theobromin with a phosphoroushalogen compound and isolating the resultant 7-methyl-2-6-dichloropurin,then treating the latter with an alkali and isolating the resultant 7-methyl-6- oity-B-chloropurin, th'cn metliy-lating the latter andisolating the resultant 1-7-dimethyl- G-oxy-Z-chloropurin and finallytreating the latter compound with a mineral acid.

In testimony whereof I have allixed my signature in presence of twowitnesses.

EMIL FISCHER.

Witnesses:

LORENZ Ans, l n. Ans.

